Exploring the Multifaceted Potential of Sildenafil in Medicine

Phosphodiesterase type 5 (PDE5) is pivotal in cellular signalling, regulating cyclic guanosine monophosphate (cGMP) levels crucial for smooth muscle relaxation and vasodilation. By targeting cGMP for degradation, PDE5 inhibits sustained vasodilation. PDE5 operates in diverse anatomical regions, with its upregulation linked to various pathologies, including cancer and neurodegenerative diseases. Sildenafil, a selective PDE5 inhibitor, is prescribed for erectile dysfunction and pulmonary arterial hypertension. However, considering the extensive roles of PDE5, sildenafil might be useful in other pathologies. This review aims to comprehensively explore sildenafil’s therapeutic potential across medicine, addressing a gap in the current literature. Recognising sildenafil’s broader potential may unveil new treatment avenues, optimising existing approaches and broadening its clinical application.


Introduction
Sildenafil is the first oral medication approved by the United States Food and Drug Administration (FDA) for the therapeutic management of erectile dysfunction (ED) [1,2].
Originally developed with the intention of treating hypertension and angina pectoris, it showed no efficacy in phase 1 clinical studies, including patients with these pathologies.However, it induced a distinct pharmacological response in these individuals, inducing significant penile erection [1,3].This accidental discovery led to the patenting of sildenafil by Pfizer in 1996, and, two years later, sildenafil received approval for the treatment of ED.Subsequently, several other uses of this pharmaceutical agent have been discovered [4].
Sildenafil is a highly effective and specific inhibitor of phosphodiesterase type 5 (PDE5) [5,6].There are several types of phosphodiesterases, but only three (PDE5, PDE6, and PDE9) specifically hydrolyse cyclic guanosine monophosphate (cGMP) over cyclic adenosine monophosphate (cAMP) [7,8].It hydrolyses the phosphodiesterase linkage and facilitates the catalytic conversion of cGMP to inactive 5 -guanosine monophosphate (GMP), hence regulating several physiological processes within the body [9], such as neuroprotection, antinociception, synaptic plasticity, calcium homeostasis, and vasodilation (Figure 1) [10].cGMP is involved in these processes through the activation of ion channels or cGMP-dependent protein kinases or through its interaction with PDE [9].Nitric oxide (NO) promotes cGMP production in the target cell.NO and cGMP are integral constituents of a signalling transduction cascade that operates through autocrine, paracrine, and potentially endocrine mechanisms.The NO/cGMP/PDE5 axis has been implicated in various illnesses, including neurological disorders, pulmonary arterial hypertension, cardiomyopathy, cancer, ED, and lower urinary tract syndrome [8,[11][12][13][14].
activation of ion channels or cGMP-dependent protein kinases or through its interaction with PDE [9].Nitric oxide (NO) promotes cGMP production in the target cell.NO and cGMP are integral constituents of a signalling transduction cascade that operates through autocrine, paracrine, and potentially endocrine mechanisms.The NO/cGMP/PDE5 axis has been implicated in various illnesses, including neurological disorders, pulmonary arteria hypertension, cardiomyopathy, cancer, ED, and lower urinary tract syndrome [8,11-14].Additionally, sildenafil might possess other mechanisms of action and, consequently, supplementary therapeutic effects.Thus, sildenafil shows promising results in the treatment of neurodegenerative diseases through the activation of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α), following the accumulation of cGMP to inactive 5′-guanosine monophosphate (GMP), hence the body [9], such as neuroprotection, antinociception, synaptic (Figure 1) [10].cGMP is involved in these processes through the otein kinases or through its interaction with PDE Sildenafil also exhibits anti-inflammatory and neuroprotective properties, potentially mediated through the regulation of the AMP-activated protein kinase (AMPK)/nuclear factor of kappa light polypeptide gene enhancer in the B-cell inhibitor alpha (IKβα)/nuclear factor kappa B (NFκB) signalling pathway [19].Furthermore, endothelial NO synthase (eNOS) contributes to the neuroprotective mechanism of sildenafil by promoting the activation of AMPK [19,20].The potential of PDE5 inhibitors to treat chronic pain is supported by their ability to counteract the downregulation of angiopoietin 1 expression, a crucial factor involved in vascular stability and neurite development, within cultured dorsal root ganglion neurons [21,22].
Sildenafil might enhance the susceptibility of various types of tumour cells to the cytotoxic impact of chemotherapeutic agents [23].This enhancement is achieved through the promotion of apoptosis, which is mediated by the downregulation of B-cell lymphoma-extralarge (Bcl-xL) and Fas-associated phosphatase-1 (FAP-1) expression, increased generation of reactive oxygen species (ROS), and upregulation of caspase-3, 8, and 9 activities [23][24][25].
The primary aim of this narrative review is to comprehensively investigate and synthesise the diverse therapeutic potentials of sildenafil within the field of medicine, as no such review currently exists.Understanding the broader potential of sildenafil can have implications for clinical practice.It may lead to the identification of new treatment options or the optimisation of existing ones, potentially expanding the range of conditions for which the drug could be considered.In summary, a review of the multifaceted potential of sildenafil in medicine serves as a valuable tool for consolidating existing knowledge, identifying new opportunities for research and clinical application, and potentially improving patient care.

Materials and Method
PUBMED was used to search the literature for the most relevant articles containing in vitro and in vivo preclinical and clinical findings on the effect of sildenafil in various conditions other than ED and PAH.We limited the search to articles published in English between 2015 and 2023.We did, however, investigate previous relevant research.We used the following keywords and MeSH terms: "sildenafil" AND "pain", "sildenafil" AND "Alzheimer" OR " Alzheimer disease", "sildenafil" AND "Raynaud's" OR "Raynaud's phenomenon", "sildenafil" AND "digital ulcer", "sildenafil" AND "wound healing", "sildenafil" AND "cancer", "sildenafil" AND "depression", "sildenafil" AND "retinopathy", "sildenafil" AND "renal" OR "renal disease" OR "kidney" OR "kidney disease" OR "nephropathy", "sildenafil" AND "gastrointestinal" OR "gastrointestinal disease", "sildenafil" AND "cardiovascular" OR "cardiovascular disease", "sildenafil" AND "lung" OR "lung disease".We selected the most appropriate studies after analysis and cross-checking.A literature study was also conducted to present the important characteristics of sildenafil pharmacokinetics, side effects, and current indications.We used the following keywords and MeSH terms: "sildenafil" AND "pharmacokinetics" OR "side effects" OR "indications" OR "erectile disfunction" OR "ED" OR "pulmonary arterial hypertension" OR "PAH".

Sildenafil Pharmacokinetic Profile and Associated Adverse Reactions
Sildenafil citrate is rapidly absorbed from the gastrointestinal tract, reaching maximum plasma concentration approximately 30-120 min (with a median of 60 min) after oral administration.The absorption rate of sildenafil citrate is reduced when taken with food (particularly fatty foods) [26][27][28][29][30]. Along with its primary circulating N-desmethyl metabolite, sildenafil citrate exhibits a binding affinity of around 96% to plasma proteins [26,27,31].It is mainly metabolised through the hepatic microsomal isoenzyme cytochrome P (CYP)3A4, with a slight contribution from the hepatic isoenzymes CYP2C9.Sildenafil citrate has 16 known metabolites.The primary metabolite, N-desmethyl sildenafil, exhibits a PDE selectivity profile comparable to that of sildenafil and an in vitro PDE5 potency roughly half that of the parent medication.The N-desmethyl metabolite is metabolised further, having a terminal half-life of about 4 h.Sildenafil citrate is a mild inhibitor of drug-metabolising enzymes, with CYP2C9 being the most inhibited [28,30,32].Sildenafil citrate is mainly eliminated as metabolites in the faeces, accounting for approximately 80% of the orally taken dose.A smaller proportion is excreted in the urine, representing approximately 13% of the orally supplied dose.Its half-life ranges from 3 to 5 h [26,27,31].
The adverse effects of sildenafil are typically mild-to-moderate in severity and of a brief duration.Among the most frequent adverse reactions associated with the use of sildenafil are headaches, flushing, dyspepsia, and visual disturbances [31].Mechanistically, these effects can be attributed to the vasodilatory properties of sildenafil.This vasodilation, although therapeutically beneficial, may cause headaches and flushing due to changes in blood flow.Additionally, altered retinal sensitivity to light may contribute to visual disturbances.Gastrointestinal effects, such as dyspepsia, may be linked to the presence of PDE5 in the smooth muscle of the gastrointestinal tract.Understanding these underlying mechanisms is crucial for both clinicians and researchers to optimise the therapeutic benefits of sildenafil while mitigating its associated adverse reactions [26,27,31].Continued research in this area will undoubtedly refine our comprehension of the intricate pharmacological profile of sildenafil, further enhancing its clinical utility [26,27].Sildenafil's systemic vasodilation may result in a transient decrease in blood pressure, particularly when coadministered with nitrate-based medications.This hemodynamic effect underscores the importance of cautious prescribing, especially in patients with a history of myocardial infarction or unstable angina.It is crucial for healthcare providers to conduct a thorough cardiovascular assessment before prescribing sildenafil, ensuring a balanced consideration of its benefits against potential risks in individuals with underlying cardiovascular issues.Regular monitoring and personalised treatment plans remain integral in minimising the cardiovascular risks associated with sildenafil use [26,27].

Current Indications
Sildenafil is commonly utilised as a PDE5 inhibitor for two main indications.

Erectile Dysfunction (ED)
ED is a prevalent medical condition observed in males, and its frequency and occurrence rise with age.It is associated with diminished overall health and the coexistence of other medical conditions [33].ED refers to the incapacity to attain or sustain an erection that is considered adequate for engaging in sexual activity [34].The global occurrence of ED ranges from 4 to 66 cases per 1000 males per year [33,[35][36][37][38].In Europe, according to the European Male Ageing Study, ED prevalence ranges from 6% to 64% across various age groups.The prevalence of ED was found to increase with age, with an average prevalence of 30% [39].Furthermore, the prevalence of ED appears to be higher in the United States, as well as in Eastern and Southeastern Asian countries, when compared to Europe or South America [40].
The NO-cGMP pathway serves as the principal mechanism for penile erection in primates, including humans.Sexual arousal activates neurological pathways, triggering the release of NO directly into the corpus cavernosum of the penis from both neurons and endothelial cells [11,41].The biological stimulus responsible for initiating penile erection is cGMP, which then activates protein kinase G (PKG), responsible for the reduction of intracellular calcium levels.This reduction leads to the relaxation of arterial and trabecular smooth muscle, which subsequently causes arterial dilatation, venous constriction, and the attainment of penile erection stiffness [41,42].PDE5 is the predominant PDE enzyme found in the corpus cavernosum, which facilitates the degradation of cGMP through the process of hydrolysis [9].A reduction in NO levels may lead to ED [38].
The efficacy of sildenafil and other PDE5 inhibitors is widely recognised as the most successful approach for managing ED due to its high efficacy and remarkable lack of substantial adverse effects [43,44].

Pulmonary Arterial Hypertension (PAH)
PAH is characterised by elevated blood pressure in the pulmonary arteries.The walls of the pulmonary arteries become narrowed, thickened, or stiff, leading to increased resistance to blood flow.This elevated resistance eventually leads to right heart failure if left untreated.The Sixth World Symposium on PAH (2022) established a mean pulmonary artery pressure (mPAP) threshold exceeding 20 mmHg as the criterion for defining PAH [45].The worldwide prevalence of PAH is significant, affecting around 1% of the global population [46].
There are various strategies for treating endothelial dysfunction.They usually aim to enhance the bioavailability of NO or the amounts of cGMP within cells.Subsequently, PDE5 inhibitors are frequently used for the management of PAH [42], being approved for its treatment in adults and children starting at the age of 1 year [8].For PDE5 inhibitors to exhibit efficacy, it is imperative that there be an adequate level of activity within the NO/soluble guanylate cyclase (sGC)/cGMP pathway.In cases where NO is inadequately produced, an alternative approach should be used, such as sGC stimulators that are not dependent on NO [42].
The FDA specifically designates sildenafil for the therapeutic management of group 1 PAH [31], a chronic and progressive disorder characterised by the development of vascular abnormalities within the pulmonary circulation [46].The addition of sildenafil to epoprostenol therapy can lead to a delay in clinical worsening in patients with New York Heart Association (NYHA) Functional Class II-III symptoms and idiopathic aetiology in 71% of cases and connective tissue disease in 25% of cases [47,48].
On the other hand, the European Medicines Agency (EMA) recommends the use of sildenafil for the treatment of adult patients diagnosed with PAH who are classed as WHO functional class II (slight limitation of physical activity) and III (marked limitation of physical activity) to enhance their exercise capacity [31].Furthermore, EMA also designates sildenafil as a therapeutic option for the management of PAH in paediatric patients ranging from 1 to 17 years of age [31,49,50].

Prospective Indications
Drug repurposing continues to be a subject of great interest within the pharmaceutical and healthcare sectors, allowing the discovery of novel applications for medications licensed for other original indications [51].Once a medicine was discovered to have an off-target or a newly recognised on-target effect, it was pushed forward for commercial exploitation [52].
As mentioned above, sildenafil is currently approved for the treatment of ED and PAH.Given the varying distribution of PDE5 across organs, recent research has extensively explored the potential therapeutic effect of sildenafil in various other conditions, such as pain, cancer, Alzheimer's disease, depression, Raynaud's phenomenon, digital ulcers, wound healing, retinopathy, gastric ulcer, colitis, nephropathy, lung injuries, and ischaemia, providing novel potential clinical applications for this molecule.

Pain
Local administration of L-arginine mitigates carrageenan-induced hyperalgesia, an effect prevented by NO inhibitors.Thus, cGMP was thought to be involved in the process of antinociception [53,54].Subsequently, the analgesic effect of sildenafil was investigated using various animal models and dosages, showing a dose-dependent analgesic effect against diabetic and traumatic neuropathic pain, thermal hyperalgesia, and formalininduced pain (Table 1).Intravenously administered sildenafil raises cGMP levels and, subsequently, modulates potassium channel function, promoting gamma-aminobutyric acid (GABA) release and resulting in an antinociceptive action.Thus, GABA receptors might mediate the pharmacological activity of sildenafil [55].Additionally, PDE5 inhibitors seem to reduce chronic pain, mitigating the decrease in angiopoietin 1 expression, a critical regulator of blood vessel stability and nerve fibre growth in cultured dorsal root ganglion neurons [21,22,56].

Alzheimer Disease
Various sildenafil concentrations elicit the activation of PGC1α, triggering mitochondrial biogenesis [15,16], enhancing the production of antioxidant enzymes [17], and reducing BACE1 expression [18].Thus, sildenafil might provide substantial advantages for individuals afflicted with Alzheimer's disease.Furthermore, its vasodilatory effect might provide an additional benefit for individuals with Alzheimer's disease since they exhibit cerebral hypoperfusion [63].
Sildenafil inhibits apoptosis in neurons experiencing hypoxia and facilitates neurogenesis [64][65][66][67][68]. Thus, it might decelerate the degeneration of neurons associated with Alzheimer's disease and facilitate neurogenesis.Additionally, sildenafil enhances insulin sensitivity and reduces endothelial inflammation in individuals with diabetes.Therefore, it could potentially exert similar effects on insulin sensitivity and inflammation in the context of Alzheimer's disease [69,70].
The in vitro administration of sildenafil protected brain mitochondria against β amyloid (Aβ) and advanced glycation end product (AGEPs)-induced injuries.In vivo, the administration of sildenafil induced an upregulation of brain-derived neurotrophic factor, a reduction in reactive astrocytes and microglia, a decrease in proinflammatory cytokines and neuronal apoptosis, and an increase in neurogenesis.Furthermore, in individuals with Alzheimer's disease, sildenafil reduced aberrant spontaneous neural activity, increased cerebral blood flow, and enhanced the cerebral metabolic rate of oxygen (Table 2) [71,72].Enhanced memory, reduced amyloid plaque accumulation, mitigated inflammatory processes, and promoted neurogenesis [77].
Enhanced memory, reduced tau protein levels, inhibited the activity of GSK3β, lowered the CDK5 p25/35 ratio, and upregulated the expression of BDNF and Arc proteins [80].Reduced hippocampal JNK phosphorylation and tau phosphorylation, as well as ameliorated memory impairments [85].

Clinical studies
Alzheimer's disease (n = 10) 50 mg, orally Reduced the intrinsic neuronal activity in the right hippocampus [87].

Systemic Sclerosis-Associated Raynaud's Disease and Digital Ulcer
The pathophysiology of systemic sclerosis-induced vasculopathy includes reduced levels of NO.Subsequently, topical preparations that result in NO release induce a notable vasodilation in patients with this pathology [89,90].The utilisation of a specific inhibitor targeting PDE5, such as sildenafil, is also an effective therapeutic approach for managing vascular disease in individuals with systemic sclerosis, considering that they have the ability to enhance the levels of NO and sustain peripheral blood circulation [91,92].Clinical trials demonstrated that administration of sildenafil positively impacts the healing process of ischaemic digital ulcers in individuals diagnosed with systemic sclerosis, while in patients with Raynaud's phenomenon, it decreases the severity, frequency, and duration of the disease (Table 3) [72,93,94].Significantly increased peripheral blood circulation and reduced the intensity and occurrence of Raynaud's syndrome [101].

Wound Healing
The treatment of chronic wounds continues to be a challenge in the medical field [107,108].Tissue injury initiates a series of reparative processes aimed at restoring the structural integrity and functionality of the affected tissue [109], including enhancement of the clotting process, mitigation of oxidative stress, formation of new blood vessels, endothelial cell growth, and tissue remodelling [92].NO seems to regulate some of these actions, leading to its recognition and utilisation as a biomarker for wound healing [110].Moreover, deficiencies in inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) have been linked to impaired wound healing [111,112].Subsequently, sildenafil has been extensively studied in the field of wound healing, particularly in relation to its role in preserving the viability of skin flaps (Table 4).

Population Dosage Results
Wistar rats with incisions of the dorsal backs 10 mg/kg bw, orally The extent of skin flap necrosis was smaller in the sildenafil-treated groups than in the control group, albeit without statistical significance [113].
Sprague-Dawley rats with incisions of the dorsal backs 9 mg/kg, i.p.
A notable reduction in dead tissue and blood flow stagnation within the flap was observed in rats treated with sildenafil [114].

Population Dosage Results
Wistar rats with incisions of the dorsal backs 10 mg/kg bw, orally Increased the vascularisation of the skin flap [115].
Streptozotocin-induced diabetic Wistar rats with incisions of the dorsal backs 5% sildenafil-containing ointments Significantly decreased wound area in both non-diabetic and diabetic rats, especially during the first stages of wound healing [116].
Wistar female rats with incisions of the abdominal wall 10 mg/kg, orally Enhanced both the breaking strength of the abdominal fascia and the process of neovascularisation [117].
Increased the levels of tissue hydroxyproline, collagen, nitrite, and total protein content [119].
Wistar rats with incisions of the dorsal backs 10 mg/kg bw, orally Decreased the size of full thickness defects [120].
Regulated cellular activity during the initial stages of wound healing reducing lymphocyte numbers and increasing monocytes [122].
Streptozotocin-induced diabetic Wistar rats with incisions of the dorsal backs 10 mg/kg bw, orally Inhibited the diabetic ulcerative process, reduced pain perception, and promoted wound healing [123].
Cross-breed street dogs with incisions in all skin layers on the anterior brachial region

mg
Increased the development of granulosa tissue and capillary network; enhanced fibroblast proliferation [109].

Retinopathy
Other than its effects on PDE5, sildenafil also inhibits, to a smaller extent (about 10% of the activity of PDE5), PDE6, which is exclusively found in photoreceptor cells, being involved in phototransduction.Hence, it is plausible that the ocular manifestations associated with sildenafil use result from the suppression of PDE-6 activity [124,125].PDE5 is found in the blood arteries of the choroid and retina [126].Subsequently, sildenafil induces NO-induced vasodilation, particularly of the choroidal blood vessels, enhancing eye blood flow.This effect is probably achieved by the vasodilation process mediated by NO [127].Furthermore, NO inhibits retinal vascular obliteration and the consequent development of proliferative retinopathies [128].
Animal studies demonstrated that sildenafil also reduced retinal vascular obliteration and neovascularisation.Additionally, it reduced the concentration of vascular endothelial growth factor (VEGF) in the ocular tissues, inhibited the progression of ischaemia injury, and reduced the thickness of the outer plexiform layer (Table 5).Thus, PDE5 inhibitors have the potential to impact disorders characterised by augmented choroidal thickness or choroidal and/or retinal ischaemia [129].

Cancer
PDE5 expression is elevated in various types of human carcinomas, such as urinary bladder tumours, metastatic breast cancers, and non-small cell lung cancers [133][134][135], possibly being involved in tumourigenesis.Hence, the suppression of PDE5 activity might result in antineoplastic properties [136].
Cyclic nucleotide second messengers, namely cGMP and cAMP, exhibit substrate affinity in the low micromolar range for ATP-binding cassette sub-family C member 4/multidrug resistance-associated protein 4 (ABCC4/MRP4) and ATP-binding cassette sub-family C member 5/multidrug resistance-associated protein 5 (ABCC5/MRP5).Sildenafil effectively suppresses the efflux function of ABCC4 and ABCC5 transporters [137,138].Shi et al. demonstrated that sildenafil has inhibitory effects on ABC (ATP-binding cassette) transporters, specifically ABCB1 (ATP-binding cassette sub-family B) and ABCG2 (ATP-binding cassette sub-family G), and reverses multidrug resistance in cancer cells [139].
Numerous preclinical studies have documented the utilisation of sildenafil in conjunction with chemotherapeutic drugs for the management of diverse types of cancer (Table 6).Sildenafil has exhibited its efficacy in augmenting the delivery of anticancer drugs by leveraging the enhanced permeation retention (EPR) effect, leading to a substantial increase in drug concentrations within tumours and consequent induction of cellular apoptosis [23].Furthermore, sildenafil has been shown to have a role in the regulation and enhancement of chemotherapeutic drugs in several cancer types.This phenomenon has been demonstrated in numerous in vitro and in vivo studies, wherein the downregulation of Bcl-xL expression; the promotion of ROS generation; the phosphorylation of BCL2-associated agonist of cell death (BAD) and B-cell lymphoma protein 2 (Bcl-2); the upregulation of caspase-3, 8, and 9 activities; the arrest of cells at the G0/G1 cell cycle phase; the circumvention of cancer cell resistance by inhibiting various ABC transporters through the elevation of cGMP; and the augmentation of autophagosome and autolysosome levels collectively induce apoptotic cell death in tumour cells [23,25,140].The combination treatment resulted in tumour cell apoptosis through the reversal of ABC-transporter-mediated multidrug resistance and the downregulation of Nrf2 and ABCC1 [140].

Breast cancer
Albino female mice injected with Ehrlich ascites carcinoma cells 5 mg/kg, orally Reduced tumour volume; decreased the levels of angiogenin, TNF-α, and the expression of vascular endothelial growth factor; and increased caspase-3 levels [142].
Enhanced the anticancer activity of cisplatin [142].
Decreased the number of tumour cells; reduced their viability, growth rate, and ability to proliferate; and increased apoptosis [147].

Colorectal cancer
Dextran-sulfate sodium (DSS)-induced colitis C57BI/6J male mice 5.7 mg/kg bw, in drinking water The administration of sildenafil resulted in a 50% reduction in the number of colon polyps [148].

Malignant melanoma
Mice expressing the human ret transgene in melanocytes 20 mg/kg bw, in drinking water Decreased the levels of IL-1β, IL-6, VEGF, S100A9, and myeloid-derived suppressor cells.Reduced the immunosuppressive capabilities of myeloid-derived suppressor cells [149].

Clinical studies
Type of cancer/Population Dosage Results

Prostate cancer
Patients with ED N/A Reduced likelihood of receiving a diagnosis of prostate cancer [150].In addition, clinical trials have been conducted to investigate the efficacy of sildenafil in the treatment of various forms of cancer (Table 6).The predominant focus of clinical research has been on the utilisation of sildenafil as a chemoadjuvant to improve its pharmacokinetic properties and to mitigate the adverse effects commonly associated with chemotherapy, specifically ED and cardiotoxicity.

Depression
Despite being primarily intended for peripheral tissue activity, sildenafil has the ability to traverse the blood-brain barrier (BBB) and impact central PDE5 activity, exhibiting various effects within the central nervous system, including the promotion of neurogenesis, augmentation of memory, mitigation of learning impairment, and neuroprotection [154].Unsurprisingly, the utilisation of sildenafil to target PDE5 has emerged as a novel therapeutic approach in the management of various neurological and neuropsychiatric disorders [44], including depression.There is a strong correlation between depression and ED, with each condition mutually influencing and exacerbating the other.Consequently, failure may occur if one disease is treated while neglecting the other [155].Additionally, ED can occur as an adverse effect of some antidepressant drugs [156].Sexual dysfunction is also a prevalent symptom of major depressive disorder itself and may be linked to decreased levels of testosterone [157][158][159].
Clinical and preclinical studies have demonstrated that PDE5 inhibitors are effective not just in the treatment of ED, but also in ameliorating ED-associated depression [160].Preclinical studies indicate an antidepressant effect similar to that of clinically used antidepressants.This action is believed to be mediated by the activation of oxytocin signalling pathways.Additionally, sildenafil increases the central concentrations of serotonin and noradrenaline [161,162] (Table 7).
Enhances the levels of key neurotransmitters in the brain, specifically serotonin and noradrenaline, mitigating the exacerbation of depressive symptoms [161].
Reduced the duration of immobility observed during the forced swimming test.Increased the sucrose preference and levels of prepulse inhibition.Increased GSH levels and decreased lipid peroxidation and IL-1β levels [163].
Male albino Swiss mice with restraint stress-induced depressive like behaviour 60 mg/kg bw, i.p.
Effectively restored the immobility generated by stress in the forced swim test [154].

The combination has notable
antidepressant-like effects in the forced swim test.It decreases the density of cerebral β-adrenergic receptors [164].

ED associated with depression (n = 54) N/A
Improved symptoms associated with depression, according to the Centre of Epidemiologic Studies-Depression Scale [166].
ED associated with depression in patients undergoing haemodialysis (n = 16) N/A Improved BDI scores compared to baseline [155].
ED associated with mild-to-moderate untreated depressive symptoms (n = 202)

ED associated with depression and idiopathic Parkinson's disease (n = 33) 50 mg, orally
Significantly reduced depression symptoms in 75% of the patients [160].

Renal Diseases
Cyclic nucleotide signal transduction pathways are a burgeoning area of study in the field of kidney disease, with ongoing emphasis on the targeted inhibition of PDE5 [167].Modulation of the cGMP-dependent protein kinase 1-phosphodiesterase (cGMP-cGK1-PDE) signalling pathway may be renoprotective and could lead to the development of innovative therapeutic approaches for chronic kidney disease.Subsequently, PDE5 inhibitors have been recognised as a prospective therapeutic alternative for various forms of renal injuries [168].
Multiple mechanisms have been postulated to play a role in counteracting the cascade of alterations generated by renal damage.The most extensively documented mechanisms by which PDE5 provides protection include stimulation of NO production via NOS activation, improvement of medullary blood flow, reversal of the Bcl2/Bax ratio, phosphorylation of extracellular signal-regulated kinase (ERK), activation of mitochondrial biogenesis, upregulation of renal progenitor cells, and regulation of multiple signalling pathways, including insulin/insulin-like growth factor 1 (IGF1) and nuclear factor NF-kB [169].
An elevation in ERK phosphorylation stimulates the activity of NOS, leading to an immediate release of NO [170].In the days following renal injury, energy is required for the repair process, which is supplied by the cellular mitochondria.Despite the fact that mitochondria undergo continuous regeneration, cellular damage such as sepsis and hypoxia stimulates rapid biogenesis, and PGC-1α facilitates this process.PGC-1α induces the activation of nuclear respiratory factors 1 and 2, which subsequently stimulate mitochondrial transcription factor A, activating DNA (deoxyribonucleic acid) transcription within the mitochondria [16,171].
However, the protective effect of PDE5 operates via an alternative pathway.PDE5 increases cGMP, which stimulates PKG, which, in turn, opens mitochondrial KATP channels (ATP-sensitive potassium channel), causing Mg 2+ release and depolarisation of the mitochondrial inner membrane.A depolarised membrane leads to a decrease in Ca 2+ influx, which subsequently inhibits cellular death.An elevated concentration of Mg 2+ decreases ROS and p38 mitogen-activated protein kinase (MAPK) activation, both of which are implicated in apoptosis [170,172,173].
Preclinical studies indicate that the administration of sildenafil improved renal function, decreasing the levels of oxidative stress indicators, such as malondialdehyde (MDA) and pro-inflammatory cytokines [174,175].Furthermore, clinical studies further support this effect, that the administration of sildenafil decreases serum creatinine levels and increases the glomerular filtration rate.Additionally, sildenafil considerably reduces albuminuria, as well as haemoglobin A1c (HbA1c) levels (Table 8) [176,177].
Iopromide-induced nephropathy in Wistar male rats 10 mg/kg bw, orally Improved structural kidney damage, exhibiting a protective potential greater than that of N-acetyl cysteine [179].
Streptozotocin-induced diabetes in Sprague-Dawley male rats 3 mg/kg bw, in drinking water Rats given sildenafil had a lower kidney-to-body weight ratio.Reduced urinary albumin excretion, renal cortical 8-OHdG levels, renal nitrotyrosine protein expression, and positive iNOS and ED-1 staining in glomeruli and tubule interstitium [180].Enhanced renal function by lowering triglyceride levels and increasing the number of podocytes [185].
Adenine-induced chronic kidney disease in Sprague-Dawley rats 0.1, 0.5, or 2.5 mg/kg bw, orally Reduced the plasma concentration of the antioxidant indices in a dose-dependent manner.Reduced the levels of indoxyl sulfate, cytokine sclerostin, and neutrophil gelatinaseassociated lipocalin [186].
Increased creatinine clearance; decreased blood urea nitrogen and uric acid levels.Inhibited the elevation in thiobarbituric acid reactive substances and superoxide anion generation, while attenuating the decrease in GSH levels through the activation of PPAR-γ receptors [191].
5/6 nephrectomy in Wistar rats 5 mg/kg, orally Effectively mitigated single nephron hyperfiltration and hypertension, inhibited the remodelling of renal arterioles, reduced systemic hypertension and proteinuria, enhanced the excretion of cGMP and nitrite/nitrate in urine, reduced oxidative stress, and ameliorated histological damage in the remaining kidney [192].
Enhanced the recovery of renal injury by activating ERK, inducing the synthesis of iNOS and eNOS, and reducing the ratio of Bax to Bcl-2 [170].
Alloxan-induced diabetic nephropathy in Wistar male rats 3 mg/kg bw, orally Reduced blood levels of urea and creatinine and decreased urinary albumin excretion.Increased levels of cGMP, antioxidant enzymes, and testosterone [194].
Deoxycorticosterone acetate-salt induced hypertension in Sprague-Dawley rats 50 mg/kg bw, orally Reduced creatinine clearance and increased albumin-to-creatinine ratio.Reduced glomerulosclerosis and tubulointerstitial fibrosis.Inhibited the upregulation of ED-1, TGF-β1, and Bax, and the downregulation of Bcl-2 in the renal tissue [195].
Streptozotocin-induced diabetes in Sprague-Dawley rats 3 mg/kg bw, in drinking water Decreased plasma concentrations of urea, creatinine, MDA, and NO.Increased GSH, Gpx, SOD, and CAT levels, as well as total antioxidant capacity [175].
Partial unilateral ureteral obstruction in Wistar rats 1 mg/kg bw, orally Sildenafil exhibited a protective effect against tubular apoptosis [196].

Population Dosage Results
Renovascular hypertension induced by the two-kidney-one-clip-operation in NO-GC1 KO mice 100 mg/kg bw, orally Elevated cGMP levels, enhanced sensitivity to NO, and reduced systolic blood pressure [198].
Left renal artery clamping in C57BL/6 mice 40 mg/kg, orally Reduced left and right kidney hypertrophy, as well as systolic blood pressure, heart rate, and intrarenal angiotensin I/II, while increasing plasma angiotensin 1-7 and NO levels [199].
Increased renal blood flow and NO production, while reducing proteinuria, IL-18 levels, cortical expression of endothelin-1, iNOS, and inflammatory cell infiltration.Prevented phenotypic alterations in proximal tubular cells [202].
Right-left nephrectomy White pigs 100 mg/kg bw, orally Increased right ventricular function, NO levels, and decreased right ventricular resistance [203].
Right-left nephrectomy minipigs 100 mg/kg bw, orally Increased right ventricular function, NO levels, and lowered renal vascular resistance.Reduced tubular oedema; improved endothelial cell integrity and mitochondrial ultrastructure [204].
Enhanced RBF and urine cGMP levels and lowered intrarenal resistance and sCr [172].
Folic acid induced acute renal injury in New Zealand white rabbits 0.3 mg/kg bw, i.p.
Upregulated the expression of COX1 and Tfam at mRNA level.Increased mtDNA copy number and downregulated KIM-1 levels [16].Significantly reduced albuminuria and HbA1c levels [177].

Gastrointestinal Diseases
Gastric ulcers arise due to the harmful effects of acid and pepsin [206].The stomach typically maintains a delicate equilibrium involving various components (such as defensive agents, the mucus bicarbonate barrier, surface epithelial cells, mucosal regeneration, blood circulation, acid-base balance, and epidermal growth factor) to counteract the effects of acid and pepsin present in the luminal content [207].The equilibrium is typically disrupted due to Helicobacter pylori infection or prolonged use of nonsteroidal anti-inflammatory medicines (NSAIDs) [208].NO exerts a substantial impact on the generation of mucosal resistance and repair [209], effectively safeguarding against stomach mucosal injury [210].Consequently, sildenafil facilitates ulcer repair.
Inflammatory bowel diseases, such as ulcerative colitis, are chronic conditions of unknown origin characterised by significant inflammation of the digestive tract [211].Their pathogenesis comprises a complex interplay among genetic, immunological, and environmental variables.During the acute episodes of inflammation, there is an increase in inflammatory cells at the intestinal level, leading to excessive synthesis of proinflammatory mediators, including cytokines, eicosanoids, ROS, and nitrogen metabolites [212][213][214].Sildenafil exerts anti-inflammatory effects by preventing lipid peroxidation, cytokine release, and oxidant generation [215,216].
Preclinical studies examined the therapeutic potential of sildenafil against various gastrointestinal diseases (Table 9), demonstrating that it effectively prevents ulceration by increasing the concentration of NO within the gastric tissue.Additionally, sildenafil enhances levels of antioxidant enzymes, reduces gastric acid secretion, decreases levels of proinflammatory cytokines, and increases the level of glutathione (GSH) [72,216,217].
Table 9. Preclinical and clinical studies evaluating the effects of sildenafil in gastrointestinal diseases.

Animal Model Dosage Results/Reference
Ethanol-induced gastric damage in Wistar male rats 1 mg/kg bw, orally Protected against stomach damage by activating the NO/cGMP/K(ATP) pathway [217].
Indomethacin-induced gastric mucosal damage in Wistar male rats 5, 10 mg/kg bw, orally Protected the stomach mucosa against the aggressive impact of indomethacin by increasing NO levels and inhibiting lipid peroxidation [217].Protected the stomach mucosa, mitigating indomethacin-induced damage [218].
Acetic acid-induced gastric ulcer in Sprague-Dawley rats 5, 10 mg/kg bw, orally Reduced inflammation and enhanced the healing response in the stomach mucosa [208].
Cysteamine-induced duodenal ulcer in Wistar male rats 25 mg/kg bw, orally Reduced oxidative stress and ameliorated the lesions observed in the duodenal mucosa [219].
Indomethacin-induced gastric ulcer in Swiss male rats 5, 25, 50 mg/kg bw, orally Exhibited a dose-dependent gastroprotective effect, decreasing ROS levels, enhancing NO and antioxidant enzymes levels, improving stomach cellular viability, and restoring variables associated with gastroprotection [220].
Indomethacin-induced gastric ulcer in Wistar male rats Sildenafil 10 mg/kg bw, orally + ranitidine 50 mg/kg bw, orally The combination exhibited antiapoptotic action on the stomach mucosa [222].
Resulted in the preservation of colon microarchitecture and a decrease in lipid peroxidation, MPO activity, TNF-α, and IL-1β levels; increased GSH levels [216].
Trinitrobenzenesulphonic acid-induced colitis in Sprague-Dawley rats 25 mg/kg bw, orally Reduced the colonic levels of MDA, MPO, CL, and TNF-α, while concurrently increasing the amount of GSH [211].

Cardiovascular Diseases
Extensive studies have been conducted on the possible application of sildenafil in the field of cardiovascular disease.Seven of the eleven major PDE subtypes-PDE1, 2, 3, 4, 5, 8, and 9-are expressed in the heart, and their diverse effects on cAMP and cGMP signalling in distinct cell types, including cardiomyocytes, provide therapeutic prospects to combat heart disease [226].PDE5 is abundantly expressed in isolated canine or murine ventricular cardiomyocytes, and it is strongly expressed in both experimental and human heart disease.PDE5 inhibition should have the potential to alter heart function, contributing to the treatment of a range of cardiovascular illnesses [42].
The vasodilatory effects of PDE5 inhibitors have positive effects on vascular coagulopathy and enhance endothelial functioning in various regions of the body [227].The presence of PDE5 antibodies has been detected in coronary vascular smooth muscle cells, it seems that healthy myocardium does not exhibit significant expression of this enzyme [8].Nonetheless, in cases of congestive heart failure and right ventricular hypertrophy, the activation of angiotensin II in vascular smooth muscle cells results in an increase in PDE5 levels, thereby leading to a decrease in cGMP/PKG reactivity [228].
A strong correlation has been established between ED and endothelial dysfunction, indicating that ED might serve as an external indicator for various underlying cardiovascular diseases.Sildenafil enhances endothelial function in medical disorders such as diabetes and congestive heart failure and enhances perfusion and oxygen tension within the vasculature holding potential for addressing ischaemia/reperfusion injury, including myocardial infarction and stroke [1,[229][230][231].
Preclinical and clinical trials demonstrate the cardioprotective effects associated with the inhibition of PDE5 in individuals diagnosed with established cardiovascular disease.In animal models, sildenafil enhanced both systolic and diastolic cardiac function, reduced cardiac hypertrophy and apoptosis of cardiomyocytes, and lowered the susceptibility to post-ischaemic arrhythmia [72,232,233].In individuals diagnosed with heart failure, the administration of sildenafil decreased pulmonary artery pressure and alleviated dyspnoea.Additionally, it improved brachial artery flow-mediated dilatation and boosted breathing during physical exertion [234].Moreover, in patients diagnosed with chronic stable left ventricular failure, sildenafil has demonstrated improvements in left ventricular ejection fraction and performance on the 6 min walking test (Table 10) [235].
Table 10.Preclinical and clinical studies evaluating the effects of sildenafil in cardiovascular diseases.

Population Dosage Results
Adult ischaemic cardiomyocytes derived from WT mice 1 µM Significantly decreased the number of trypan blue-positive necrotic cells [236].

Ischaemic hearts of Wistar rats 3 µM
Elevated cGMP levels and concomitantly reduced the extent of the infarct [238].
Ischaemic isolated hearts of Wistar rats (Langendorff mode) 10, 20, 50, and 200 nM Enhanced the coronary flow at lower levels of coronary perfusion pressure across all doses [239].

Piglet model of cardiopulmonary bypass and arrest 10 nM
Restored ATP levels, enhanced energy charge, and modified release of hypoxanthine and inosine [240].
C57BL6/J mice with heart hypertrophy 100 mg/kg bw, orally Improved both systolic and diastolic function, reducing cardiac hypertrophy and cardiomyocyte apoptosis [232].Significant inhibition of cardiac hypertrophy and left ventricular systolic dysfunction [242].
Decreased the extent of myocardial infarction following an episode of ischaemia [236].
ICR mice exposed to global ischaemia followed by reperfusion 0.71 mg/kg bw, i.p Decreased the extent of the infarct through the activation of mitoKCa and mitoKATP [243].
ICR mice exposed to ischaemia followed by reperfusion 0.7 mg/kg bw, i.p.
Reduced the extent of the infarct, increasing both iNOS and eNOS levels [244].
ICR mice exposed to descending coronary artery occlusion followed by reperfusion 0.7 mg/kg bw, i.p.
Elevated cardiac SIRT1 activity, leading to a reduction in the extent of the myocardial infarction [245].
Ensured the preservation of fractional shortening.Reduced the left ventricular end-diastolic dilatation, fibrosis, and apoptosis [246].
ICR mice subjected to myocardial infarction through the closure of the left anterior descending coronary artery 0.71 mg/kg bw, i.p.
Reduced ischaemic injury score.Increased the expression of eNOS and iNOS proteins and the ratio of Bcl-2 to Bax.Reduced apoptosis and the left ventricular end-diastolic diameter [247].
Dystrophin-deficient mice 80 mg/kg bw, orally Mitigated impairments in heart function.Improved both the myocardial performance index and the ratio of early diastolic filling velocity to late diastolic filling velocity [248].
iNOS knockout and eNOS knockout C57BL6/J mice exposed to ischaemia followed by reperfusion Improved mitochondrial respiration and increased the expression of PGC1α mRNA in the myocardium [250].
Significantly reduced the size of infarcted regions [251].

Population Dosage Results
Wistar rats exposed to heterotopic cardiac transplantation 0.7 mg/kg bw, i.v.
Enhanced both systolic and diastolic function of the myocardium following a three-hour period of arrest.Determined a notable translocation of CPK delta [252].
Wistar rats exposed to ischaemia and reperfusion 50 mg/kg bw, orally Suppressed the significant elevation of MDA levels [253].
Sprague-Dawley rats exposed to left anterior descending coronary artery occlusion followed by reperfusion 0.7 mg/kg bw, i.v.
Increased the density of capillaries and arterioles, enhancing blood flow.Increased the expression of VEGF and Ang-1 at mRNA levels during the initial reperfusion period [254].
Mongrel dogs exposed to blockage of the anterior descending coronary artery 2 mg/kg bw, orally Prolonged the QT interval, particularly in the presence of ischaemic conditions [233].
Piglets exposed to untreated ventricular fibrillation, which was afterwards followed by open-chest cardiopulmonary resuscitation 0.5 mg/kg, i.p.
The administration of sildenafil resulted in a shift towards aerobic metabolism in energy use.
Increased the levels of ATP and ADP, while decreasing the levels of lactate in the myocardial tissue [255].
Pigs exposed to ventricular fibrillation and cardiopulmonary resuscitation 0.5 mg/kg bw, i.p.
Partially reduced the elevated levels of plasma Ang II and Ang (1-7 Elicited both immediate and delayed protective effects against ischaemia-reperfusion injury by the activation of mitochondrial KATP channels [259].
New Zealand rabbits exposed to ischaemia through the blockage of coronary arteries.0.71 mg/kg bw, i.v.Reduced the size of the infarct [260].

Clinical studies
Patients with chronic heart failure (n = 46) 50 mg, orally Decreased pulmonary artery pressure and alleviated dyspnoea, while improving brachial artery flow-mediated dilatation and enhancing breathing during physical exertion [234].

Lung Diseases
While sildenafil has received approval for the treatment of PAH, studies have demonstrated its positive effects on various respiratory conditions, such as bronchopulmonary dysplasia and cystic fibrosis, while other conditions, such as asthma, had a negative impact.Furthermore, research conducted on animals has demonstrated that the administration of sildenafil in the treatment of PAH is associated with a decrease in several inflammatory mediators and the regulation of several intracellular signalling molecules, including MAPK, NF-kβ, and ERK [267].Preclinical and clinical research indicates that sildenafil could potentially serve as a novel therapeutic approach for lung disorders, particularly those characterised by an inflammatory reaction (Table 11).

Summary
Our narrative review focused on summarising the potential clinical applications of sildenafil.Sildenafil, recognised for its vasodilatory effects, has shown potential therapeutic applications beyond ED and PAH, extending into various medical domains.In the realm of pain management, studies suggest that sildenafil may modulate nociceptive pathways.Its ability to increase pain reaction latency in animal models with neuropathic pain, such as those induced by diabetes, indicates a potential role in alleviating chronic pain [22,58].The underlying mechanism involves the activation of the cGMP pathway, which is implicated in pain signal processing.Sildenafil's influence on this pathway may contribute to the attenuation of pain responses, providing a foundation for exploring its utility in clinical settings addressing chronic pain conditions [53,54].
Emerging evidence also points to the neuroprotective effects of sildenafil in neurodegenerative diseases such as Alzheimer's.The drug's impact on cerebral blood flow and its ability to reduce oxidative stress and inflammation in the brain suggest potential benefits in mitigating neurodegenerative processes.The modulation of cGMP-dependent pathways and enhancement of neurotrophic factors are proposed mechanisms through which sildenafil may exert neuroprotective effects.This opens avenues for research into the use of sildenafil as a potential adjunctive therapy for neurodegenerative disorders [69,77,88].
In the context of systemic sclerosis-associated Raynaud's disease and digital ulcers, sildenafil's vasodilatory properties become particularly relevant.By inhibiting PDE5, the enzyme responsible for cGMP degradation, sildenafil prolongs the vasodilatory effects of NO.This mechanism improves blood flow, offering potential relief for patients with systemic sclerosis where vascular complications are prominent [91,92].The positive impact on digital ulcers, a common complication in systemic sclerosis, suggests a role for sildenafil in managing the vascular manifestations of autoimmune diseases.The precise mechanisms involve enhanced vasodilation and improved microcirculation, showcasing the multifaceted therapeutic potential of sildenafil in systemic sclerosisassociated complications [72,93,94].
In the realm of cancer, studies propose that sildenafil's inhibition of PDE5 could impact tumour growth [136].Modulation of the cGMP signalling pathway influences angiogenesis and immune responses, enhancing the efficacy of chemotherapy and presenting a potential avenue for adjunctive cancer therapy [23].In depression, sildenafil's neuroprotective effects and its influence on neurotransmitter systems, including serotonin and dopamine, have been explored [154,161].By enhancing cGMP signalling in the brain, sildenafil may exhibit antidepressant effects, paving the way for further investigations into its role in mood disorders.
Renal diseases, marked by impaired blood flow and inflammation, may benefit from sildenafil's vasodilatory and anti-inflammatory properties.The drug's ability to enhance renal blood flow through the relaxation of vascular smooth muscle cells offers a potential therapeutic avenue for conditions such as chronic kidney disease [169,202].Gastrointestinal diseases, particularly those involving impaired blood perfusion, could also be targeted by sildenafil.The drug's vasodilatory effects may aid in improving blood flow to the gastrointestinal tract, potentially mitigating complications in conditions such as inflammatory bowel disease [215,216].Additionally, sildenafil's impact on ischaemia/reperfusion injury holds promise in cardiovascular events such as myocardial infarction and stroke.The vasodilation induced by sildenafil can enhance blood flow during reperfusion, potentially reducing tissue damage and inflammation [1,[229][230][231]244].These multifaceted applications of sildenafil underscore its potential as a versatile therapeutic agent beyond its well-established roles, necessitating further research to unravel the full extent of its clinical utility.
While preclinical studies have demonstrated promising outcomes, including mechanisms of action and potential benefits, several limitations impede a straightforward transition to clinical applications.Preclinical trials often involve animal models, which may not fully mirror the complexities of human physiology and pathology.Additionally, variations in dosages, administration methods, and experimental designs among preclinical studies contribute to a lack of standardised protocols.Furthermore, the diverse nature of human diseases requires careful consideration of factors such as patient variability, comorbidities, and long-term effects, which may not be fully captured in preclinical settings.
Supplementary limitations in the current body of research include a potential bias towards positive outcomes in published studies, which may not reflect the entire spectrum of findings and could skew the overall perception of sildenafil's efficacy.Additionally, there is a need for more comprehensive investigations into potential adverse effects and interactions with other medications, especially in the context of chronic usage.Addressing these limitations is crucial for establishing the safety and effectiveness of sildenafil in diverse clinical scenarios.
Consequently, the current gap between preclinical evidence and clinical trials underscores the need for rigorous, well-designed clinical studies to validate the safety, efficacy, and optimal dosages of sildenafil in these diverse medical indications.Bridging this gap is crucial to ascertain the true therapeutic potential of sildenafil and to establish evidencebased guidelines for its application in clinical settings.

Conclusions
In conclusion, our comprehensive review highlights the diverse and promising therapeutic potential of sildenafil beyond its well-established uses.From its role in pain management, neurodegenerative diseases, and systemic sclerosis-associated complications to its impact on cancer, depression, and various organ-specific diseases, sildenafil emerges as a multifaceted therapeutic agent.However, rigorous, well-designed clinical studies are essential to guide evidence-based guidelines for the nuanced application of sildenafil in diverse clinical settings, ensuring its potential as a versatile therapeutic agent is realised to its fullest extent.

Figure 1 .
Figure 1.The mechanism of action of sildenafil and its subsequent potential indications (X-inhibition; increased created with BioRender version, Bio Rad 2023).

Figure 1 .
Figure 1.The mechanism of action of sildenafil and its subsequent potential indications (Xinhibition;

0
.06 mg/kg bw injection into the LV lumen The administration of sildenafil resulted in a notable decrease in the extent of myocardial infarction.This indicates that the acute cardioprotective effects of low-dose sildenafil are not reliant on eNOS, iNOS, or cGMP [249].PGC1α −/− mice subjected to transverse aortic constriction-induced pressure overload 200 mg/kg bw, orally Enhanced cardiac function and remodelling.

Table 1 .
Preclinical studies that evaluated the effect of sildenafil on pain.

Table 2 .
Preclinical and clinical studies that evaluated the effect of sildenafil on Alzheimer's disease.

Table 3 .
Clinical studies evaluating the effect of sildenafil in digital ulcers and Raynaud's syndrome.

Table 4 .
Preclinical studies evaluating the effect of sildenafil in wound healing.

Table 5 .
Preclinical studies evaluating the benefits of sildenafil in retinopathy.

Table 6 .
Preclinical and clinical studies that evaluated the benefits of sildenafil in cancer.

Table 8 .
Preclinical and clinical studies evaluating the effects of sildenafil in renal diseases.

Table 11 .
Preclinical and clinical studies evaluating the effects of sildenafil in lung diseases.